The Origin of the Variola Virus

Abstract

The question of the origin of smallpox, one of the major menaces to humankind, is a constant concern for the scientific community. Smallpox is caused by the agent referred to as the variola virus (VARV), which belongs to the genus Orthopoxvirus. In the last century, smallpox was declared eradicated from the human community; however, the mechanisms responsible for the emergence of new dangerous pathogens have yet to be unraveled. Evolutionary analyses of the molecular biological genomic data of various orthopoxviruses, involving a wide range of epidemiological and historical information about smallpox, have made it possible to date the emergence of VARV. Comparisons of the VARV genome to the genomes of the most closely related orthopoxviruses and the examination of the distribution their natural hosts’ ranges suggest that VARV emerged 3000 to 4000 years ago in the east of the African continent. The VARV evolution rate has been estimated to be approximately 2 × 10−6 substitutions/site/year for the central conserved genomic region and 4 × 10−6 substitutions/site/year for the synonymous substitutions in the genome. Presumably, the introduction of camels to Africa and the concurrent changes to the climate were the particular factors that triggered the divergent evolution of a cowpox-like ancestral virus and thereby led to the emergence of VARV.

17th Century Variola Virus Reveals the Recent History of Smallpox

“…Under the model with the narrowest posterior distribution (strict molecular clock and constant population size), the evolutionary rate of VARV is estimated to be between 7.3 and 9.6 × 10 −6 nucleotide substitutions per site per year (mean of 8.5 × 10 −6 subs/site/year). This is similar to previous estimates of the evolutionary dynamics of VARV inferred using tip-date based methods on more modern strains only [4, 6, 20] and to rates previously estimated in myxomavirus (another poxvirus) in European rabbits, for which longitudinal sequence data is available for a sampling period of ∼50 years [21]. Finally, we observed overlapping substitution rates (range of credible intervals of 5.6 to 9.5 × 10 −6 subs/site/year) when VD21 was excluded from the analysis, further suggesting that our estimates of the nucleotide substitution rate are robust.…”

“…An initial regression of root-to-tip genetic distances against year of sampling provided clear evidence for clock-like molecular evolution in VARV (R 2  = 0.79). Importantly, strong temporal structure (R 2  = 0.80) was also observed when VD21 was excluded from the regression analysis, indicating that it was not simply the function of a single ancient sequence and that it characterizes VARV evolution as a whole [4, 6, 20]. Similarly clock-like evolution was observed using a Bayesian approach, with extensive overlap in estimates of substitution rates and divergence times under a range of molecular-clock and demographic models (Figure 3; Table S3).…”

“…Although there have been claims of smallpox in Egypt, India, and China dating back millennia [1, 2, 3, 4], the timescale of emergence of the causative agent, variola virus (VARV), and how it evolved in the context of increasingly widespread immunization, have proven controversial [4, 5, 6, 7, 8, 9]. In particular, some molecular-clock-based studies have suggested that key events in VARV evolution only occurred during the last two centuries [4, 5, 6] and hence in apparent conflict with anecdotal historical reports, although it is difficult to distinguish smallpox from other pustular rashes by description alone. To address these issues, we captured, sequenced, and reconstructed a draft genome of an ancient strain of VARV, sampled from a Lithuanian child mummy dating between 1643 and 1665 and close to the time of several documented European epidemics [1, 2, 10].…”

Genomic characterization of a novel poxvirus from a flying fox: evidence for a new genus?

“…As such, a key concern with PTPV is whether or not it has zoonotic potential, but due to the inability to isolate the virus, in vitro testing in human-derived cell lines could not be undertaken as an initial predictive test. However, there are several indications that PTPV may have already undergone extensive host-specific adaptation: (1) frequently, there is general host specificity of poxviruses within a genus (PTPV likely represents a new genus); (2) relatively few non-essential genes that are usually associated with host specificity (Babkin & Babkina, 2015) are shared with other viruses (e.g. the presence of only a single ankyrin-like protein); (3) the relatively small genome of PTPV; and (4) the presence of 29 unique ORFs.…”

“…Furthermore, many poxviruses within a genus have evolved to become specific to a particular host. Within the orthopoxviruses, variola virus (VARV; the agent of smallpox) and camelpox (CMLV) are thought to have evolved from a larger cowpox-like (CPXV) ancestral virus and that the restriction of host-range has been accompanied by the loss of some non-essential genes (Babkin & Babkina, 2015).…”